In the U.S., major depression ranks first among all causes of disability and second after heart disease as a cause of healthy years lost to premature mortality and disability (See, Hyman and Rudorfer, “Depressive and Bipolar Mood Disorders,” in Dale and Federman (eds.), Scientific American Medicine, Healtheon/WebMD, New York, N.Y. [2000]). Indeed, approximately 10 percent of the population experiences at least one depressive episode that would benefit from treatment, while 5 percent would be classified as having severe and disabling symptoms of depression (See, Hyman and Rudorfer, supra).
While the prevalence of unipolar depression (major depression) in the U.S. is 5-10 percent, with women having approximately a two-fold greater risk than men, the prevalence of bipolar disorder (manic-depressive illness) is approximately 1 percent, is less variable, and affects men and women equally (See, Hyman and Rudorfer, Supra). There is a strong familial association for unipolar, as well as bipolar disorder. For example, the familial nature of bipolar disorder is associated with a 5 to 10-fold increased risk in first-degree relatives above the 1 percent risk in the general population (See, Hyman and Rudorfer, supra). Bipolar disorder often begins in young adulthood (e.g., second or third decade of life), although childhood onset is increasingly being recognized. Late onset is less common, but can even occur in the elderly. In rare cases, patients may have only a single manic episode. However, the vast majority of patients have recurrent episodes of illness, with the rate of cycling between mania and depression varying widely among individuals, and the episodes becoming more frequent with age. Between episodes of depression and mania, the majority of patients are symptom-free, although as many as one-third of patients exhibit residual symptoms.
Patients affected by bipolar disorder have had at least one manic or hypomanic (mild mania) episode. However, at the time of diagnosis, they may never have had a depressive episode, according to the DSM-IV criteria. The diagnosis is supported by family history data and observational studies. According to the DSM-IV, patients with full manias and depression are indicated as having “bipolar I disorder,” while patients with hypomanias and depressions are described as having “bipolar II disorder.” Onset of episodes tends to be acute, with symptoms developing over days to weeks. The depressive episodes of bipolar patients are indistinguishable from those of patients with unipolar disorder. Thus, misdiagnosis of bipolar disorder is common. Indeed, as many as 40 percent of bipolar patients are initially misdiagnosed (See, Hyman and Rudorfer, supra). It is also not uncommon for clinicians to misclassify bipolar patients as depressed or schizophrenic on the basis of their mental status. However, it is important to make a proper diagnosis, as administration of some drugs can seriously worsen the patient's clinical picture.
In addition to the problems associated with diagnosis, treatment of bipolar disorder can be problematic. Indeed, it has been estimated that 5 percent of patients experience chronic unremitting symptoms despite treatment (See, Hyman and Rudorfer, supra). Mania requires prompt treatment because it can rapidly worsen, resulting in poor judgment that endangers interpersonal relationships, jobs, and finances. Management is founded upon medication, provision of a low-stimulation environment, and protecting the patient from undertaking potentially harmful activities. Initial management of acute mania is often best accomplished through hospitalization. Thus, the management of bipolar disorder can be expensive, intrusive, and difficult. In addition, despite the now routine use of maintenance treatment for bipolar disorder, up to 90 percent of patients experience at least one relapse within 5 years of their original diagnosis (See, Hyman and Rudorfer, supra). Thus, it is clear that improved methods and compositions for the diagnosis and treatment of psychiatric diseases such as bipolar disorder are needed.